DiGeorge Syndrome (22q11.2 Deletion Syndrome)

1. Clinical Overview

Summary

DiGeorge Syndrome, now more accurately termed 22q11.2 Deletion Syndrome (22q11DS), is the most common chromosomal microdeletion disorder in humans, with an estimated prevalence of 1 in 4,000 live births. [1] This multisystem disorder results from a hemizygous deletion of chromosome 22 at the q11.2 locus, encompassing approximately 30-40 genes within a 3 megabase (Mb) critical region. [2]

The syndrome represents a disorder of pharyngeal pouch development, particularly affecting derivatives of the third and fourth pharyngeal pouches, leading to the classic constellation of features remembered by the mnemonic CATCH-22: Cardiac defects (conotruncal anomalies), Abnormal facies, Thymic aplasia or hypoplasia, Cleft palate, and Hypocalcemia secondary to parathyroid hypoplasia, all occurring due to the deletion on chromosome 22. [3]

The phenotypic spectrum is remarkably variable, ranging from severely affected neonates with life-threatening cardiac defects and profound T-cell immunodeficiency (classic DiGeorge phenotype) to mildly affected adults diagnosed incidentally when their affected child is identified. [4] This phenotypic heterogeneity occurs even within affected families carrying identical deletions, suggesting significant influence of modifier genes, epigenetic factors, and stochastic developmental events. [5]

Historical Context

Historical Note: Dr. Angelo DiGeorge (1965) The syndrome was first described by Dr. Angelo DiGeorge, an American paediatric endocrinologist, who reported three infants with congenital absence of the thymus and parathyroid glands presenting with hypocalcemia and recurrent infections. His seminal observation linked these seemingly disparate findings to a common embryological origin. [6]

Dr. Robert Shprintzen (1978) Subsequently, Dr. Shprintzen described Velocardiofacial Syndrome (VCFS), characterised by velopharyngeal insufficiency, cardiac anomalies, and distinctive facial features. Molecular studies in the 1990s demonstrated that DiGeorge syndrome, VCFS, and several other named conditions (Conotruncal Anomaly Face Syndrome, Cayler Cardiofacial Syndrome) all result from deletions at 22q11.2, representing variable expression of a single genetic disorder. [7]

The Sedlackova Discovery In 1955, Czech physician Eva Sedlackova described "velofacial hypoplasia" in children—essentially VCFS. Her work, published in Czech, remained unknown to Western medicine until recently due to Cold War barriers, demonstrating how geopolitical divisions can impede scientific progress. [8]

The "CATCH-22" Mnemonic

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2. Epidemiology

Incidence and Prevalence

The reported birth prevalence of 22q11.2 deletion syndrome is approximately 1 in 4,000 live births based on ascertainment through severe cardiac defects and neonatal presentations. [1] However, this likely represents significant underascertainment. Population-based studies and prenatal screening cohorts suggest the true prevalence may be as high as 1 in 1,000-2,000 when mildly affected individuals are included. [9]

Demographics

• Equal sex distribution: Males and females are affected equally [1]
• No ethnic predilection: Reported across all ethnic groups worldwide [3]
• Second most common cause: Of developmental delay after Down syndrome [10]
• Most common microdeletion: The 22q11.2 deletion is the most frequent chromosomal microdeletion syndrome in humans [1]

Genetic Epidemiology

The deletion occurs de novo in approximately 90% of cases, arising as a new mutation during parental gametogenesis (usually paternal origin). [2] In the remaining 10%, the deletion is inherited from an affected parent in an autosomal dominant pattern, conferring a 50% risk of transmission to offspring. [4]

Importantly, transmitting parents may have subtle or unrecognised features of the syndrome. Careful phenotypic evaluation and parental testing are essential components of genetic counselling. Studies have shown that approximately 6-10% of parents of apparently de novo cases are actually carriers with mild phenotypes. [11]

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3. Genetics and Molecular Pathogenesis

The 22q11.2 Deletion

The syndrome results from a hemizygous deletion at chromosome 22q11.2. The majority (85%) of patients carry a typical 3 Mb deletion encompassing approximately 40-50 genes, including the critical gene TBX1. [2] The remaining 15% have atypical deletions that are either smaller (1.5 Mb) or have different breakpoints, but all include the TBX1 gene. [12]

Mechanism of Deletion: Non-Allelic Homologous Recombination

The 22q11.2 region is flanked by Low Copy Repeats (LCRs), also called segmental duplications. These highly homologous sequences (> 97% sequence identity) predispose to Non-Allelic Homologous Recombination (NAHR) during meiosis, resulting in deletions or duplications. [12]

Chromosome 22q11.2 Structure:

LCR-A    ────[3Mb Deletion Region]────    LCR-D
   │                                        │
   └────── Misalignment during meiosis ─────┘
                       ↓
              NAHR → Deletion

The TBX1 Gene: Master Regulator

TBX1 (T-box transcription factor 1) is the primary candidate gene responsible for the major features of 22q11DS. [13]

Evidence for TBX1 as the critical gene:

1. Mouse Tbx1 knockouts recapitulate the cardiac, thymic, parathyroid, and craniofacial phenotypes [13]
2. Rare point mutations in TBX1 cause a DiGeorge-like phenotype in patients without the typical deletion [14]
3. TBX1 is expressed in pharyngeal arch mesoderm and endoderm during critical developmental windows [13]

TBX1 Function:

• Regulates pharyngeal arch and pouch development
• Controls migration and differentiation of neural crest cells
• Essential for fourth pharyngeal arch artery development (→ aortic arch)
• Required for thymic and parathyroid organogenesis [13]

Haploinsufficiency

The pathogenic mechanism is haploinsufficiency: loss of one TBX1 copy results in only 50% of normal protein production, which is insufficient for normal embryonic development. This explains why the syndrome manifests despite retention of one normal allele. [2]

Other Genes in the Deleted Region

The COMT Gene and Psychiatric Risk

The COMT gene, encoding catechol-O-methyltransferase, is located within the deleted region. COMT metabolises catecholamines including dopamine in the prefrontal cortex. Hemizygosity for COMT, combined with specific polymorphisms in the remaining allele, may contribute to the elevated psychiatric risk seen in 22q11DS, particularly the 25-30% lifetime risk of schizophrenia. [15]

22q11.2 Duplication Syndrome

The same NAHR mechanism can produce duplications at 22q11.2. The phenotype of 22q11.2 duplication syndrome overlaps partially with the deletion syndrome but is generally milder and more variable. [12] Importantly, FISH testing cannot distinguish duplications from normal—chromosomal microarray is required. [16]

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4. Embryology and Pathophysiology

Pharyngeal Apparatus Development

The pharyngeal (branchial) apparatus consists of paired arches, pouches, grooves, and membranes that develop during weeks 4-8 of embryonic life. The third and fourth pharyngeal pouches are particularly affected in 22q11DS. [6]

Third Pharyngeal Pouch Derivatives:

• Thymus (ventral wing): T-cell development and maturation
• Inferior parathyroids (dorsal wing): Calcium homeostasis

Fourth Pharyngeal Pouch Derivatives:

• Superior parathyroids (dorsal wing): Calcium homeostasis
• Ultimobranchial body → Parafollicular C-cells (calcitonin production)

Neural Crest Cell Contribution

Neural crest cells (NCCs) arising from the dorsal neural tube migrate into the pharyngeal arches and contribute to:

• Craniofacial skeleton
• Connective tissue of thymus and parathyroids
• Conotruncal septum (dividing the truncus arteriosus into aorta and pulmonary artery)
• Aortic arch smooth muscle [6]

TBX1 regulates NCC migration and pharyngeal arch morphogenesis. Haploinsufficiency disrupts these processes, explaining the constellation of affected structures. [13]

Cardiac Development and Conotruncal Defects

The fourth pharyngeal arch artery normally forms the arch of the aorta on the left and contributes to the subclavian artery on the right. Failure of fourth arch development results in:

• Interrupted Aortic Arch (Type B): The aortic arch is discontinuous between the left carotid and left subclavian arteries
• Aberrant subclavian artery: Right subclavian arising from descending aorta
• Vascular rings: From abnormal arch configuration

The neural crest-derived conotruncal septum divides the truncus arteriosus. Abnormal septation causes:

• Truncus arteriosus: Failure of septation
• Tetralogy of Fallot: Malaligned septum
• VSD (conoventricular type): Deficient septum [17]

Thymic Development and Immunodeficiency

The thymic primordium develops from the third pharyngeal pouch and descends into the anterior mediastinum. In 22q11DS:

• Thymic hypoplasia (most common): Small but functional thymus with reduced T-cell output
• Thymic aplasia (less than 1%): Complete absence of thymic tissue resulting in severe T-cell immunodeficiency (Complete DiGeorge) [18]

T-cell development occurs within the thymus, where bone marrow-derived progenitors undergo positive and negative selection to generate a diverse, self-tolerant T-cell repertoire. Without thymic tissue, T-cell development is profoundly impaired. [18]

Parathyroid Aplasia and Hypocalcemia

Parathyroid glands develop from the third and fourth pharyngeal pouches. Hypoplasia or aplasia results in:

• Reduced or absent PTH secretion
• Inability to mobilise calcium from bone
• Inability to stimulate renal calcium reabsorption
• Inability to activate vitamin D in the kidney
• Result: Hypocalcemia and hyperphosphatemia [19]

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5. Clinical Features: Comprehensive Review

Cardiac Defects (75-80%)

Congenital heart defects are present in approximately 75-80% of patients with 22q11DS. [1] The cardiac anomalies are predominantly conotruncal in nature, reflecting the embryological dependence of the outflow tract on neural crest cell contribution. [17]

Clinical Pearl: Interrupted Aortic Arch Type B If you diagnose Interrupted Aortic Arch Type B (interruption between the left carotid and left subclavian arteries), this is 22q11DS until proven otherwise. Approximately 50-60% of all Type B IAA cases are caused by 22q11.2 deletion. [17]

TOF with Pulmonary Atresia and MAPCAs

A particularly severe cardiac phenotype in 22q11DS is Tetralogy of Fallot with pulmonary atresia and Major Aortopulmonary Collateral Arteries (MAPCAs). These patients have:

• Absent native pulmonary blood flow
• Pulmonary circulation dependent on systemic-to-pulmonary collaterals
• Complex surgical management requiring unifocalization procedures
• Higher surgical mortality [17]

Facial Features (> 90%)

The facial phenotype in 22q11DS is often subtle and may be missed without specific training. Features become more apparent with age. [3]

Thymic Aplasia/Hypoplasia and Immunodeficiency (75%)

Classification of T-cell Deficiency

Complete DiGeorge Syndrome

Complete DiGeorge syndrome represents a T-cell negative SCID phenotype and is a medical emergency. [18]

Features:

• Absolute T-cell counts less than 50 cells/μL or less than 1% of total lymphocytes
• Absent thymic shadow on chest X-ray
• Absent naive T-cells (CD45RA+)
• High susceptibility to opportunistic infections (PCP, CMV, fungal)
• Fatal without immune reconstitution (thymus transplant or HSCT)

Critical Management Points:

• ISOLATE immediately (reverse barrier nursing)
• NO LIVE VACCINES (BCG, rotavirus, MMR, varicella)
• IRRADIATED blood products only (prevent TA-GVHD)
• CMV-negative blood products
• PCP prophylaxis (co-trimoxazole)
• Urgent immunology referral
• Consider thymus transplantation [18]

Partial DiGeorge Syndrome

Most patients (> 99%) have partial DiGeorge with:

• Reduced T-cell numbers that typically improve with age ("immune reconstitution")
• Generally adequate immune function for daily life
• Increased susceptibility to viral infections in infancy
• May have recurrent sinopulmonary infections
• Live vaccines can usually be given after age 1 if CD4 counts adequate (> 500 cells/μL or > 15% of lymphocytes) [20]

Autoimmune Manifestations

Paradoxically, T-cell dysregulation in 22q11DS leads to increased autoimmune disease, likely due to defective thymic negative selection:

• Autoimmune cytopenias: ITP (12%), AIHA, neutropenia
• Juvenile Idiopathic Arthritis: Increased prevalence
• Thyroid autoimmunity: Hypothyroidism (Hashimoto's), Graves' disease
• Evans syndrome: Combined ITP and AIHA—should raise suspicion for 22q11DS [20]

Palatal Abnormalities (70%)

Palatal abnormalities are extremely common and frequently underdiagnosed. [3]

Submucous Cleft Palate: What to Look For

The classic triad of submucous cleft:

1. Bifid uvula: Split or notched uvula
2. Zona pellucida: Bluish/translucent midline of soft palate (indicating muscle separation)
3. Notch in posterior hard palate: Palpable on examination

Clinical Pearl: Velopharyngeal Insufficiency (VPI) VPI causes hypernasality (air escapes through nose during speech), particularly on pressure consonants ("p"

• "b"
• "d"
• "t"). Patients cannot blow up a balloon or whistle. Infants may have nasal regurgitation of milk. [3]

Contraindicated Procedure: Adenoidectomy

Adenoidectomy is contraindicated in 22q11DS unless absolutely necessary and only after specialist plastics/ENT assessment. Removal of adenoid tissue worsens VPI by increasing the velopharyngeal gap that must be closed during speech. [3]

Hypocalcemia (50-60%)

Hypocalcemia results from parathyroid hypoplasia or aplasia leading to hypoparathyroidism. [19]

Patterns of Hypocalcemia

Clinical Manifestations of Hypocalcemia

Neonatal:

• Jitteriness
• Seizures (may be the presenting feature)
• Tetany
• Poor feeding
• Apnoea

Children/Adults:

• Paraesthesias (perioral, fingers)
• Muscle cramps
• Tetany
• Laryngospasm (stridor—emergency!)
• Seizures
• Prolonged QTc on ECG

Clinical Pearl: "The Calcium Seizure" If a neonate presents with seizures, check the calcium first. If hypocalcemia is present, examine for a cardiac murmur and check the lymphocyte count. This triad should prompt urgent testing for 22q11DS.

Investigation of Hypocalcemia

Management of Hypocalcemia

Acute (Symptomatic/Seizures):

1. IV Calcium Gluconate 10%: 0.5 mL/kg (0.11 mmol/kg) over 10-15 minutes with cardiac monitoring
2. Avoid extravasation (causes tissue necrosis)
3. Repeat as needed
4. ECG monitoring (risk of bradycardia)

Maintenance:

1. Oral Calcium: Calcium carbonate or calcium citrate (50-100 mg/kg/day elemental calcium in divided doses)
2. Active Vitamin D: Alfacalcidol (1α-hydroxyvitamin D3) 25-50 ng/kg/day OR Calcitriol 10-20 ng/kg/day
   • Active vitamin D is required because PTH normally activates 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in the kidney
   • Without PTH, this activation is impaired
3. Target: Serum calcium low-normal range (avoid hypercalcemia and hypercalciuria)
4. Monitor: Calcium, phosphate, renal function, urine calcium:creatinine ratio [19]

Neurodevelopmental and Psychiatric Features

22q11DS is associated with a broad spectrum of neurodevelopmental and psychiatric disorders. [15]

Learning Difficulties

Attention and Behaviour

• ADHD: 35-55% prevalence
• Autism Spectrum Disorder: 20-40% meet criteria
• Anxiety disorders: Very common from childhood
• Social difficulties: Pragmatic language impairment, difficulty with peer relationships [15]

Psychiatric Disorders (Adolescence/Adulthood)

22q11DS confers the highest known genetic risk for schizophrenia:

Critical Warning: Cannabis Cannabis use significantly increases the risk of psychosis in 22q11DS, with onset at earlier ages and worse outcomes. All patients and families must be counselled about this risk. [15]

Screening for Psychosis (Age 14+)

Annual screening questions:

1. "Do you ever hear voices or sounds that other people don't hear?"
2. "Do you ever feel that people are watching you, following you, or trying to harm you?"
3. "Have you noticed changes in your thinking or concentration?"
4. "Have you stopped seeing friends or doing activities you used to enjoy?"

Renal and Urological Abnormalities (30%)

Routine renal ultrasound is recommended at diagnosis:

• Renal agenesis (single kidney)
• Multicystic dysplastic kidney
• Duplex collecting system
• Vesicoureteral reflux
• Horseshoe kidney [3]

Skeletal Abnormalities

Caution: Cervical Spine Instability Upper cervical spine anomalies occur in 20-40% of patients. Consider cervical spine evaluation before general anaesthesia or contact sports. [3]

Feeding and Gastrointestinal

• Feeding difficulties: Common in infancy (60-70%)
• Dysphagia: Due to pharyngeal hypotonia, VPI, and occasionally vascular ring
• Gastro-oesophageal reflux: Very common
• Constipation: Common, may relate to hypotonia
• May require gastrostomy: For nutrition and airway protection in severe cases [3]

Hearing Loss

Aggressive management of conductive hearing loss (grommets) is important for speech and language development. [3]

Dental Abnormalities

• Enamel hypoplasia (from neonatal hypocalcemia)
• Delayed tooth eruption
• Missing teeth
• Small teeth
• High caries risk (combination of enamel defects, dietary issues, poor hygiene in those with intellectual disability) [3]

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6. Diagnosis

Clinical Suspicion

22q11DS should be suspected in any patient with:

• Conotruncal cardiac defect (especially IAA Type B, truncus arteriosus, TOF)
• Hypocalcemia (especially neonatal or unexplained)
• Characteristic facial features
• Cleft palate or VPI
• Thymic hypoplasia or unexplained T-cell lymphopenia
• Combination of cardiac defect with any of the above
• Unexplained learning difficulties with suggestive features

Genetic Testing

Gold Standard: Chromosomal Microarray (CMA) is the recommended first-line test. It detects the deletion in > 99% of cases, defines deletion size, and identifies other copy number variants. [16]

Prenatal Diagnosis

22q11DS can be detected prenatally:

• Indications for testing: Conotruncal cardiac defect on fetal echo, polyhydramnios with absent thymus, known affected parent
• Methods: Chorionic villus sampling (CVS) or amniocentesis with microarray
• NIPT: Some expanded NIPT panels can detect 22q11.2 deletion with reasonable sensitivity, though confirmatory invasive testing is recommended [16]

Newborn Screening

T-cell receptor excision circles (TRECs), measured in newborn bloodspot screening for SCID, may identify some severe cases of 22q11DS with profound T-cell lymphopenia. However, most 22q11DS patients have adequate TRECs and will not be detected by SCID screening. [18]

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7. Differential Diagnosis

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8. Management

Multidisciplinary Team Approach

22q11DS requires coordinated care from multiple specialists. A designated "medical home" coordinator is essential. [4]

Core MDT Members:

• Clinical Genetics
• Cardiology
• Immunology
• Endocrinology
• ENT/Speech Pathology
• Plastic Surgery (cleft team)
• Developmental Paediatrics
• Child Psychiatry/Psychology
• General Paediatrician (coordinator)

Neonatal Period: Priorities

Priority 1: Cardiac Assessment and Stabilisation

• Echocardiogram: All patients require early echocardiography
• Prostaglandin E1: If duct-dependent lesion (IAA, critical PS, truncus)
• Surgical planning: Timing based on anatomy and clinical status

Surgical Considerations:

• Higher risk of laryngeal/tracheal anomalies—anaesthetic considerations
• Hypocalcemia complicates peri-operative management
• IRRADIATED, CMV-negative blood products ONLY (risk of TA-GVHD) [17]

Priority 2: Calcium Management

All neonates should have calcium and PTH measured:

• If hypocalcemic: Treat as per protocol above
• If normocalcemic: Monitor closely, especially during illness/stress

Priority 3: Immunological Assessment

Initial workup:

• Full blood count with differential (absolute lymphocyte count)
• T-cell subsets (CD3+, CD4+, CD8+)
• Naive T-cells (CD45RA+)
• Immunoglobulins (may be low initially)
• Thymic shadow on chest X-ray

Vaccination Guidance:

Transfusion-Associated Graft-versus-Host Disease (TA-GVHD)

Why irradiated blood?

• Donor T-cells in blood products can attack recipient tissues
• Immunocompetent individuals destroy donor T-cells immediately
• 22q11DS patients (especially complete DiGeorge) cannot eliminate donor T-cells
• Donor T-cells engraft and attack recipient bone marrow, skin, gut, liver
• Mortality > 90%

Prevention:

• Gamma irradiation of all cellular blood products (25-50 Gy)
• Irradiation damages donor lymphocyte DNA, preventing proliferation
• This should be lifelong for complete DiGeorge; for partial DiGeorge, continue until confirmed immunocompetent [18]

Thymus Transplantation for Complete DiGeorge

Complete DiGeorge syndrome (athymia) is fatal without immune reconstitution. Thymus transplantation is the treatment of choice. [18]

Procedure:

1. Thymic tissue obtained from paediatric cardiac surgery donors (age less than 9 months ideal)
2. Tissue cultured for 12-21 days (depletes mature T-cells)
3. Thymic slices implanted into quadriceps muscle
4. Neovascularization and T-cell development occur over 6-12 months

Outcomes:

• 70-75% survival
• Successful T-cell reconstitution in most survivors
• Enables live vaccination after immune reconstitution [18]

Long-Term Management

Endocrine Monitoring

• Calcium and PTH: Every 6-12 months; more frequently if on treatment
• Thyroid function: Annual (autoimmune thyroid disease risk)
• Growth: Monitor for growth hormone deficiency (not common but reported)

Immunological Monitoring

• Annual T-cell subsets: Until stable in adulthood
• Immunoglobulin levels: If recurrent infections
• Vaccine responses: May have impaired antibody responses

Developmental and Educational

• Early intervention: Speech therapy, occupational therapy, physiotherapy as needed
• Educational support: Most require EHCP/statement of special educational needs
• Focus areas: Mathematics support, social skills groups, visual-spatial learning strategies

Feeding and Nutrition

• Dietitian involvement: From diagnosis
• Gastrostomy: Consider early if significant feeding difficulties/failure to thrive
• Reflux management: Often required

ENT and Speech

• Regular audiology: Screen for conductive and sensorineural loss
• Aggressive glue ear management: Low threshold for grommets
• Speech therapy: For VPI and articulation
• VPI surgery: Pharyngeal flap or sphincter pharyngoplasty if indicated (NOT adenoidectomy)

Psychiatric Monitoring

• Annual psychosocial assessment: From adolescence
• Psychosis screening: From age 14
• Low threshold for referral: Any concerning symptoms
• Avoid cannabis: Explicit counselling essential [15]

Transition to Adult Care

Transition planning should begin at age 14-16 and complete by age 18-25:

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9. Prognosis and Outcomes

Mortality

Overall mortality in 22q11DS is approximately 4-8%, driven primarily by:

1. Severe congenital heart disease (main cause of early death)
2. Complete DiGeorge syndrome (without thymus transplant)
3. Sudden cardiac death in adolescence/adulthood [4]

Long-Term Outcomes

Emerging Concerns in Adults

• Early-onset Parkinson's disease: Emerging evidence suggests increased risk [4]
• Osteoporosis: Due to chronic hypoparathyroidism
• Hypercalciuria and nephrolithiasis: Complication of calcium/vitamin D supplementation
• Cardiac valve disease: Long-term follow-up showing increased rates

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10. Genetic Counselling

For Parents of Affected Child

De novo deletion (90%):

• Recurrence risk for future pregnancies: less than 1%
• Parental testing is still recommended (some parents are mildly affected mosaics)
• Prenatal diagnosis available if desired

Inherited deletion (10%):

• One parent is affected (may be undiagnosed)
• Recurrence risk: 50% for each pregnancy
• Prenatal diagnosis strongly recommended
• Offer testing to other at-risk family members

For Affected Individuals

• Transmission risk: 50% to offspring regardless of parent's phenotype severity
• Prenatal options: CVS/amniocentesis, PGD (preimplantation genetic diagnosis)
• Highly variable expression: Affected child may be more or less severely affected than parent
• Fertility considerations: Most individuals can have children; women may need calcium monitoring during pregnancy [11]

Gonadal Mosaicism

Rarely, a parent may have the deletion only in germline cells (gonadal mosaicism) without somatic features. This can result in multiple affected offspring despite negative parental blood testing. Counsel that risk can never be reduced to zero. [11]

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11. Exam Focus: Viva Points and Common Questions

Opening Statement

"22q11.2 deletion syndrome, also known as DiGeorge syndrome, is the most common chromosomal microdeletion disorder with a prevalence of 1 in 4,000. It is caused by a hemizygous 3Mb deletion at chromosome 22q11.2, most commonly arising de novo, resulting in haploinsufficiency of the TBX1 gene. The clinical features are remembered by the CATCH-22 mnemonic: Cardiac defects (conotruncal), Abnormal facies, Thymic aplasia, Cleft palate, and Hypocalcemia. Management requires a multidisciplinary approach, and prognosis depends primarily on cardiac anatomy and immune status."

Key Numbers to Know

Common Exam Questions

Q: A neonate with Tetralogy of Fallot is found to have hypocalcemia. What is your diagnosis and next steps?

A: "This combination is highly suggestive of 22q11.2 deletion syndrome. My immediate management would include:

1. Treat hypocalcemia (IV calcium gluconate if symptomatic, oral calcium and alfacalcidol for maintenance)
2. Urgent immunology referral with T-cell subset analysis
3. Chromosomal microarray to confirm diagnosis
4. Ensure irradiated, CMV-negative blood products for any transfusions
5. Hold live vaccines pending immunological assessment
6. Multidisciplinary team involvement including genetics"

Q: What cardiac defects are associated with 22q11DS and why?

A: "The cardiac defects in 22q11DS are predominantly conotruncal, reflecting the embryological role of neural crest cells in outflow tract development. TBX1 haploinsufficiency impairs neural crest cell migration and pharyngeal arch morphogenesis. Key defects include:

• Tetralogy of Fallot (most common, 20-25%)
• Interrupted Aortic Arch Type B (pathognomonic, 50% of all IAA-B)
• Truncus arteriosus (30-40% of all truncus)
• VSD (conoventricular type)
• Vascular rings and aberrant subclavian artery"

Q: How do you manage a child with Complete DiGeorge syndrome?

A: "Complete DiGeorge is a medical emergency representing a T-cell negative SCID phenotype. Management includes:

1. Immediate isolation with reverse barrier nursing
2. Irradiated, CMV-negative blood products only
3. PCP prophylaxis with co-trimoxazole
4. Antifungal prophylaxis
5. No live vaccines (absolutely contraindicated)
6. Urgent referral for thymus transplantation, which is the treatment of choice
7. Supportive care for cardiac and endocrine manifestations"

What Gets You Failed

❌ Missing the diagnosis when presented with classic features ❌ Giving live vaccines to an immunocompromised patient ❌ Not using irradiated blood products ❌ Forgetting to check calcium in a neonate with seizures ❌ Not counselling about psychiatric risk and cannabis avoidance ❌ Performing adenoidectomy without recognising VPI risk

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12. Patient and Family Resources

Support Organisations

• Max Appeal (UK): Leading charity for 22q11.2 deletion syndrome and related conditions
• 22q11.2 Society: International professional and family organisation
• International 22q11.2 Foundation: Education and advocacy
• Syndromes Without A Name (SWAN): For families awaiting diagnosis

Key Messages for Families

"Did I cause this?" "No. This is a random genetic change that happened during egg or sperm formation. It is not caused by anything you did during pregnancy."

"Will my child be able to go to school?" "Most children attend mainstream school with appropriate support. Many children with 22q11DS do well academically, particularly in reading and verbal skills. Maths is often more challenging. An Education, Health and Care Plan (EHCP) can help ensure your child gets the right support."

"What about the mental health risks?" "There is an increased risk of psychiatric conditions, particularly in adolescence and adulthood. We monitor for this carefully, and early intervention improves outcomes. Avoiding cannabis and other drugs significantly reduces risk."

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13. Anaesthetic Considerations

Pre-operative Assessment

Patients with 22q11DS require careful pre-operative evaluation:

Specific Risks

1. Difficult intubation: Due to retrognathia, micrognathia, cervical spine anomalies
2. Subglottic stenosis: May require smaller endotracheal tube
3. Post-operative stridor: Due to laryngomalacia or hypocalcemia-induced laryngospasm
4. Hypocalcemia: May be exacerbated by citrate in blood products; monitor ionised calcium
5. Bleeding risk: If thrombocytopenia from ITP
6. Infection risk: Particularly if immunocompromised

Blood Product Requirements

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14. Monitoring and Surveillance Schedule

Paediatric Surveillance (Birth to 18 years)

Adult Surveillance (18+ years)

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15. Special Circumstances

Pregnancy in Women with 22q11DS

Pre-conception:

• Genetic counselling (50% transmission risk)
• Cardiac assessment and risk stratification
• Medication review (switch to pregnancy-safe vitamin D preparations)
• Discuss prenatal diagnosis options (CVS, amniocentesis, PGD)

During Pregnancy:

• Shared care: Obstetrics, maternal medicine, genetics, cardiology
• Calcium monitoring: Increased calcium demands; may need dose adjustment
• Fetal echo at 18-20 weeks: Screen for cardiac defects in fetus
• Mental health monitoring: Increased psychiatric risk during/after pregnancy

Delivery:

• Plan delivery location based on cardiac status and fetal risk
• Anaesthetic pre-assessment essential
• Calcium monitoring peri-delivery
• Irradiated blood products if needed

Postpartum:

• Increased psychiatric risk: monitor closely for psychosis
• Neonatal testing: Microarray if not done prenatally
• Breastfeeding: Usually safe; some medications may need adjustment

Surgery in 22q11DS Patients

Pre-operative Checklist:

• Cervical spine evaluation if not done
• Recent echocardiogram (within 6 months for cardiac patients)
• Calcium and PTH levels
• Full blood count (check for ITP)
• T-cell subsets if immunodeficiency history
• Blood bank notified: irradiated, CMV-negative products
• Anaesthetic alert documented
• Antibiotic prophylaxis if cardiac lesion requires

Dental Care

Patients with 22q11DS have increased dental needs:

Risk Factors:

• Enamel hypoplasia from neonatal hypocalcemia
• Delayed eruption
• Caries susceptibility
• Cooperation difficulties in those with intellectual disability
• Potential need for cardiac prophylaxis (if residual lesions)

Recommendations:

• Early dental registration (by age 1)
• Fluoride supplementation as per local guidelines
• 6-monthly dental reviews
• Consider GA for complex dental work if cooperation limited
• Antibiotic prophylaxis per current guidelines if indicated

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16. Research and Emerging Therapies

Current Clinical Trials

Areas of active research in 22q11DS:

1. Neurocognitive interventions: Computerised cognitive training programs
2. Psychiatric prevention: Early intervention studies for ultra-high risk psychosis
3. Cardiac outcomes: Long-term follow-up registries
4. Gene therapy: Preclinical studies on TBX1 replacement
5. Thymus-derived therapies: Cultured thymic tissue optimisation

Biomarkers Under Investigation

• Circulating microRNAs as disease severity predictors
• Neuroimaging markers for psychiatric risk
• T-cell receptor diversity as immune reconstitution marker

Future Directions

• Newborn screening: Expanded TREC screening may identify more severe cases
• Precision psychiatry: Genetic profiling to predict and prevent psychosis
• Regenerative medicine: Induced thymic organoids for immune reconstitution

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17. Quality Metrics and Guidelines

Key Guidelines

1. McDonald-McGinn DM, et al. (2015): International 22q11.2 Deletion Syndrome Consortium clinical practice guidelines [4]
2. Practical Guidelines for Managing Adults with 22q11.2 DS (Bassett et al.) [4]
3. Immune management guidelines: British Society for Immunology and ESID recommendations [20]

Discharge Checklist for New Diagnosis

• Genetic testing confirmed (microarray)
• Parental testing arranged
• Echocardiogram complete
• Calcium and PTH levels stable
• Immunology referral made
• Vaccine guidance provided (no live vaccines until cleared)
• Blood product alert documented (irradiated, CMV-negative)
• Renal ultrasound completed
• Audiology referral made
• Speech and language therapy referral
• Developmental paediatrics referral
• Genetics counselling appointment
• Support group information provided
• Follow-up appointments booked

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18. References

1. McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071. doi:10.1038/nrdp.2015.71

2. Shaikh TH, Kurahashi H, Saitta SC, et al. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum Mol Genet. 2000;9(4):489-501. doi:10.1093/hmg/9.4.489

3. Shprintzen RJ. Velo-cardio-facial syndrome: 30 Years of study. Dev Disabil Res Rev. 2008;14(1):3-10. doi:10.1002/ddrr.2

4. Bassett AS, McDonald-McGinn DM, Devriendt K, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr. 2011;159(2):332-339.e1. doi:10.1016/j.jpeds.2011.02.039

5. Swillen A, McDonald-McGinn D. Developmental trajectories in 22q11.2 deletion syndrome. Am J Med Genet C Semin Med Genet. 2015;169(2):172-181. doi:10.1002/ajmg.c.31435

6. DiGeorge AM. Congenital absence of the thymus and its immunologic consequences: concurrence with congenital hypoparathyroidism. Birth Defects Orig Artic Ser. 1968;4(1):116-121. doi:10.1007/978-1-4684-8000-7_1

7. Shprintzen RJ, Goldberg RB, Lewin ML, et al. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome. Cleft Palate J. 1978;15(1):56-62. doi:10.1597/1545-1569_1978_015_0056_ansicl_2.0.co_2

8. Burn J, Takao A, Wilson D, et al. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11. J Med Genet. 1993;30(10):822-824. doi:10.1136/jmg.30.10.822

9. Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics. 2003;112(1 Pt 1):101-107. doi:10.1542/peds.112.1.101

10. Oskarsdóttir S, Vujic M, Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden. Arch Dis Child. 2004;89(2):148-151. doi:10.1136/adc.2003.026880

11. Delio M, Guo T, McDonald-McGinn DM, et al. Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. Am J Hum Genet. 2013;92(3):439-447. doi:10.1016/j.ajhg.2013.01.018

12. Edelmann L, Pandita RK, Spiteri E, et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum Mol Genet. 1999;8(7):1157-1167. doi:10.1093/hmg/8.7.1157

13. Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet. 2001;27(3):286-291. doi:10.1038/85845

14. Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362(9393):1366-1373. doi:10.1016/S0140-6736(03)14632-6

15. Schneider M, Debbané M, Bassett AS, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2014;171(6):627-639. doi:10.1176/appi.ajp.2013.13070864

16. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764. doi:10.1016/j.ajhg.2010.04.006

17. Momma K. Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol. 2010;105(11):1617-1624. doi:10.1016/j.amjcard.2010.01.333

18. Markert ML, Devlin BH, Alexieff MJ, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007;109(10):4539-4547. doi:10.1182/blood-2006-10-048652

19. Fung WLA, Butcher NJ, Costain G, et al. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med. 2015;17(8):599-609. doi:10.1038/gim.2014.175

20. Sullivan KE, Jawad AF, Engel M, et al. Lack of correlation between impaired T cell production, immunodeficiency, and other phenotypic features in chromosome 22q11.2 deletion syndromes. Clin Immunol Immunopathol. 1998;86(2):141-146. doi:10.1006/clin.1997.4463

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Senior Editor: Dr. N. Goyal (Paediatrics & Clinical Genetics) Guideline Verification: 22q11.2 Society International Guidelines 2022 Last Updated: January 2025

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